Ferric organic compounds, uses thereof and methods of making same

ABSTRACT

The present invention discloses a novel form of ferric organic compounds, including a form of ferric citrate, which are soluble over a wider range of pH, and which have a large active surface area. The ferric organic compounds of the present invention can be delivered effectively by oral route with better delivery to treat patients suffering from hyperphosphatemia, metabolic acidosis and other disorders responsive to ferric organic compound therapy.

This application is a Continuation-In-Part application ofPCT/US2004/004646, filed on Feb. 18, 2004, published under InternationalPublication Number WO2004/074444 on Sep. 2, 2004, which claims thebenefit of U.S. Ser. Nos. 60/447,690, filed 19 Feb. 2003, and60/462,684, filed 15 Apr. 2003, and the entire contents and disclosuresof the preceding applications are incorporated by reference into thisapplication.

Throughout this application, various publications are referenced.Disclosures of these publications in their entireties are herebyincorporated by reference into this application to more fully describethe state of the art to which this invention pertains.

TECHNICAL FIELD

This invention relates to ferric organic compounds, such as ferriccitrate, methods of making the ferric organic compounds, and uses of theferric organic compounds in the treatment of various disorders.

BACKGROUND OF THE INVENTION 1) Uses of Iron Compounds

Ferric iron containing compounds are useful in the treatment of a numberof disorders, including, but not limited to, hyperphosphatemia andmetabolic acidosis. Previous studies and inventions have reported theuse of ferric compounds in binding with dietary phosphates, and suchferric compounds are potentially useful for the treatment ofhyperphosphatemia in renal failure patients (U.S. Pat. No. 5,753,706,1998; U.S. Pat. No. 6,903,235, 2005; CN1315174, 2001; Yang W. C., etal., Nephrol. Dial. Transplant 17:265:270 (2002)). Elevated amounts ofphosphate in the blood can be removed by administering compounds such asferric citrate. Once in solution, the ferric iron binds phosphate, andthe ferric phosphate compounds precipitate in the gastrointestinaltract, resulting in effective removal of dietary phosphate from thebody. It is also believed that the absorbed citrate from ferric citrateis converted to bicarbonate which corrects metabolic acidosis, acondition common in renal failure patients.

U.S. Pat. No. 5,753,706 discloses the use of ferric containing compoundsincluding ferric citrate and ferric acetate in the crystalline form, inan orally effective 1 gram dosage form, to bind to soluble dietaryphosphate, causing precipitation of phosphate as ferric or ferrousphosphates in the gastrointestinal tract thus preventing oral absorptionof soluble phosphates from dietary sources. Since the binding of ferricions to soluble phosphate in the gastrointestinal tract would requiredissolution of the orally administered ferric citrate, and since therate of dissolution of crystalline ferric citrate is slow (over 10-12hours at 37° C.), oral administration of a substantially large dose of 1g of ferric citrate is required. A related Chinese patent application(CN 1315174) also discloses a similar use of ferric citrate and relatedcompounds in an oral solution dosage form for the treatment ofhyperphosphatemia in renal failure patients.

2) Solution Chemistry of Fe(III) Compounds

Fe(III) is a lewis acid and is chemically less soluble in the stomach atpH normally below 5 than at intestinal pH normally above 7. The stomachis believed to be an important site of action for the dissolution ofFe(III) compounds. It is also believed that the stomach is also animportant site of action for Fe(III) to mediate its action in binding todietary phosphates, preventing phosphate from reaching the intestine andthus reducing the absorption of phosphates from the intestine.

SUMMARY OF THE INVENTION

In accordance with these and other objects of the invention, a briefsummary of the present invention is presented. Some simplifications andomission may be made in the following summary, which is intended tohighlight and introduce some aspects of the present invention, but notto limit its scope. Detailed descriptions of a preferred exemplaryembodiment adequate to allow those of ordinary skill in the art to makeand use the invention concepts will follow in later sections.

This invention relates to novel forms of ferric organic compounds,methods of making these compounds, and uses of these compounds in thetreatment of various disorders, including, but not limited to,hyperphosphatemia and metabolic acidosis.

The novel forms of ferric organic compounds are synthesized by adding analkaline metal hydroxide to a water soluble ferric iron salt. Thealkaline metal hydroxide can comprise sodium hydroxide, potassiumhydroxide, or any other suitable alkaline metal hydroxide. The solubleferric iron salt can comprise ferric chloride hexahydrate, or any othersuitable ferric iron salt. The alkaline metal hydroxide is added at aspecific rate and temperature to form a uniform polyiron oxo colloidalsuspension. The colloidal suspension is then washed, and solidcrystalline organic acid is added at a specific temperature to form theferric organic compound in solution. The organic acid can comprisecitric acid, acetic acid, isocitric acid, succinic acid, fumaric acid,tartaric acid, or any other suitable organic acid. The novel forms ofthe ferric organic compounds are precipitated out of solution using anorganic solvent. The organic solvent can comprise ethanol, methanol,butanol, acetone, isopropyl alcohol, tetrahydrofuran, or any othersuitable organic solvent. The resulting novel forms of the ferricorganic compounds have an enhanced dissolution rate.

In one embodiment, the novel form of ferric organic compound comprises anovel form of ferric citrate. The novel form of ferric citrate issynthesized by adding sodium hydroxide at a specific rate andtemperature to ferric chloride hexahydrate to form a uniform colloidalsuspension of ferric hydroxide. Solid crystalline citric acid is addedto the colloidal suspension and heated to a specific temperature rangeto form ferric citrate in solution. The novel form of ferric citrate isprecipitated out of solution using an organic solvent.

The novel form of ferric citrate has the formula C₆H₅O₇Fe and has novelphysical properties as determined by dissolution rates. The compound canhave an intrinsic dissolution rate range, as determined by USP (UnitedStates Pharmacopeia) intrinsic dissolution assay in water, between 1.9to 4.0 mg/cm²/min. The novel form of ferric citrate is more aqueouslysoluble in a wider range of pH than commercially available forms offerric citrate. The novel form of ferric citrate can have a large activesurface area compared to commercially available forms of ferric organiccompounds or complexes.

Because it is more soluble, the novel form of ferric organic compounds,including novel forms of ferric citrate, can be used to more effectivelydeliver ferric organic compounds by the route of oral administration topatients suffering from illnesses which are responsive to treatment withferric organic compounds, including, but not limited to,hyperphosphatemia and metabolic acidosis.

This invention relates to use of the novel form of ferric organiccompounds, including novel forms of ferric citrate to treat patientssuffering from disorders responsive to ferric organic compoundtreatment.

This invention also relates to methods of treating patients sufferingfrom disorders responsive to ferric organic compound treatment byadministering a therapeutically effective amount of ferric organiccompound to the patients.

This invention further relates to a composition for treatinghyperphosphatemia in a subject, comprising an effective amount of ferriccitrate. In an embodiment, the subject is a human being. In anotherembodiment, the amount of ferric citrate effective in treatinghyperphosphatemia is between 3 to 6 grams/day. In a further embodiment,the effective amount is 3 or 4.5 grams/day.

This invention further relates to a method for treatinghyperphosphatemia in a subject, comprising administering to said subjectan effective amount of ferric citrate. In an embodiment, the subject isa human being. In another embodiment, the amount of ferric citrateeffective in treating hyperphosphatemia in a subject is between 3 to 6grams/day. In a further embodiment, the effective amount is 3 or 4.5grams/day. It will be within the knowledge and abilities of a personhaving ordinary skill in the art to perform a dose-ranging study todetermine the effective amount of ferric organic compounds or ferriccitrate of the present invention.

DETAILED DESCRIPTION OF THE FIGURES

In drawings which illustrate specific embodiments of the invention, butwhich should not be construed as restricting the spirit or scope of theinvention in any way:

FIG. 1 is a schematic diagram outlining the method of making novel formsof ferric organic compounds according to the invention.

FIG. 2 is a plot of the dissolution profile of the novel form of ferriccitrate of the invention compared to a commercially available compound.

FIG. 3 is an isotherm graph of volume adsorbed vs. relative pressuredemonstrating BET active surface area of the novel form of ferriccitrate. Produced by Coulter SA 3100 (Serial No. z11017; SoftwareVersion 2.13; Elapsed time: 29 min.; Outgas time: 60 min.; Outgastemperature: 40° C.)

FIG. 4 is an X-ray diffraction spectra of the novel form of ferriccitrate. Range: 4.00 to 40.00 (Deg); Step Scan Rate: 0.02 Deg/min.

FIG. 5 is a thermogravimetric analysis of the novel form of ferriccitrate. Method: Heating 10° C./MIN, N2@40CC/MIN; Size: 10.5480 mg.

DETAILED DESCRIPTION OF THE INVENTION

Throughout the following description, specific details are set forth inorder to provide a more thorough understanding of the invention.However, the invention may be practiced without these particulars. Inother instances, well known elements have not been shown or described indetail to avoid unnecessarily obscuring the invention. Accordingly, thespecification and drawings are to be regarded in an illustrative, ratherthan a restrictive, sense.

This invention provides a method of synthesizing a form of ferricorganic compound which comprises obtaining a ferric iron salt; adding analkaline metal hydroxide to the ferric iron salt at a rate andtemperature effective to produce a uniform polyiron oxo suspension;isolating a precipitate from the suspension; adding an organic acid tothe precipitate; forming a ferric-organic acid solution by heating theorganic acid and the precipitate; and precipitating the form of ferricorganic compound from the ferric-organic acid solution by adding anorganic solvent to the solution.

In an embodiment, the alkaline metal hydroxide is added at a rate ofless than 20 ml/min. In another embodiment, the alkaline metal hydroxideis added at a rate of between about 10 ml/min and about 20 ml/min. In apreferred embodiment, a nominal rate of 10 to 20 ml/min is preferred.

In an embodiment, the alkaline metal hydroxide is added to the ferriciron salt at a temperature of less than 40° C. In another embodiment,the alkaline metal hydroxide is added to the ferric iron salt at atemperature between about 10° C. and about 40° C. In a preferredembodiment, a nominal temperature of 30° C. is preferred.

In an embodiment, heating the organic acid and the precipitate comprisesheating the organic acid and the precipitate to a temperature betweenabout 75° C. to about 95° C. In a preferred embodiment, the range isbetween about 80° C. and about 90° C. In another preferred embodiment, anominal temperature of 85° C. is preferred. In an embodiment,precipitating the form of ferric organic compound from theferric-organic acid solution by adding an organic solvent to thesolution comprises cooling the ferric-organic acid solution to less than30° C. before adding the organic solvent. In a preferred embodiment, theferric-organic acid solution is cooled to a nominal temperature of 20°C. In an embodiment, cooling the ferric-organic acid solution comprisescooling the ferric-organic acid solution to a temperature between about10° C. and about 30° C. In a preferred embodiment, the ferric-organicacid solution is cooled to a nominal temperature of 20° C.

In an embodiment, the ferric iron salt comprises ferric chloridehexahydrate.

In an embodiment, the organic acid includes but is not limited tosuccinic acid, fumaric acid or tartaric acid. In another embodiment, theorganic acid comprises citric acid.

In an embodiment, the alkaline metal hydroxide includes but is notlimited to sodium hydroxide or potassium hydroxide. In anotherembodiment, the alkaline metal hydroxide comprises sodium hydroxide.

In an embodiment, the organic solvent includes but is not limited toethanol, methanol, butanol, isopropyl alcohol, acetone ortetrahydrofuran.

This invention provides a method of synthesizing a form of ferriccitrate which comprises obtaining ferric chloride hexahydrate; addingsodium hydroxide to the ferric chloride hexahydrate at a rate andtemperature effective to produce a uniform polyiron oxo suspension;isolating a precipitate from the suspension; adding crystalline citricacid to the precipitate; forming a ferric-citric acid solution byheating the citric acid and the precipitate; and precipitating the formof ferric citrate from the ferric-citric acid solution by adding anorganic solvent to the solution.

In an embodiment, sodium hydroxide is added to ferric chloridehexahydrate at a rate of less than 20 ml/min. In another embodiment,sodium hydroxide is added to ferric chloride hexahydrate at a rate ofbetween about 10 ml/min and about 20 ml/min. In a preferred embodiment,a nominal rate of 10 to 20 ml/min is preferred.

In an embodiment, sodium hydroxide is added to ferric chloridehexahydrate at a temperature of less than 40° C. In another embodiment,sodium hydroxide is added to ferric chloride hexahydrate at atemperature between about 10° C. and about 40° C. In a preferredembodiment, a nominal temperature of 30° C. is preferred.

In an embodiment, the ferric-citric acid solution is formed by heatingthe citric acid and the precipitate to a temperature between about 75°C. to about 95° C. In a preferred embodiment, the range is between about80° C. and about 90° C. In another preferred embodiment, a nominaltemperature of 85° C. is preferred.

In an embodiment, precipitating the form of ferric citrate from theferric-citric acid solution by adding an organic solvent to the solutioncomprises cooling the ferric-citric acid solution to less than 30° C.before adding the organic solvent. In a preferred embodiment, theferric-organic acid solution is cooled to a nominal temperature of 20°C.

In an embodiment, cooling the ferric-citric acid solution comprisescooling the ferric-citric acid solution to a temperature between about10° C. and about 30° C. In a preferred embodiment, the ferric-organicacid solution is cooled to a nominal temperature of 20° C.

In an embodiment, the organic solvent includes but is not limited toethanol, methanol, butanol, isopropyl alcohol, acetone ortetrahydrofuran.

This invention provides a use of a form of ferric organic compound orferric citrate as describe above for treating a subject suffering from adisorder responsive to ferric organic compound therapy. In anembodiment, the subject is a human being. In another embodiment, thedisorder includes but is not limited to hyperphosphatemia or metabolicacidosis. Chen et al., New Phosphate Binding Agent: Ferric Compounds. JAm Soc Nephrol. 10(6):1274-80, 1999, reported that Ferric salts, such asferric citrate, decrease net intestinal phosphate absorption. Yang etal., An open-label, crossover study of a new phosphate-binding agent inhaemodialysis patients: ferric citrate. Nephrol Dial Transplant.17(2):265-70, 2002, reported that ferric citrate is effective and welltolerated as a treatment for hyperphosphatemia in patients.

This invention provides a method of treating a subject suffering from adisorder responsive to ferric organic compound therapy comprisingadministering to the subject a therapeutically effective amount of aferric organic compound as described above. In an embodiment, thesubject is a human being. In another embodiment, the ferric organiccompound is ferric citrate. In a further embodiment, the disorderincludes but is not limited to hyperphosphatemia or metabolic acidosis.

This invention provides a form of a ferric organic compound having anenhanced dissolution rate. In an embodiment, the said organic compoundincludes but is not limited to citric acid, acetic acid, isocitric acid,succinic acid, fumaric acid, tartaric acid or other related organiccompounds. In another embodiment, the said ferric organic compound has alarge active surface area compared to conventional ferric organiccompounds.

This invention provides a form of ferric citrate having the formulaC₆H₅O₇Fe and/or having physical properties as determined by dissolutionrates. In an embodiment, the dissolution rate, as determined by USPintrinsic dissolution assay in water, is between 1.9 to 4.0 mg/cm2/min.

This invention provides a form of ferric citrate having a BET (BrunauerEmmett Teller) active surface area exceeding 16 sq.m/g and a BET activesurface area isotherm as shown in FIG. 3.

This invention provides a form of ferric citrate having the x-raydiffraction pattern shown in FIG. 4.

This invention provides a form of ferric citrate having three transitiontemperatures as determined by thermogravimetric analysis (TGA) andhaving a TGA profile as shown in FIG. 5.

This invention provides a form of ferric citrate, wherein the form offerric citrate has a large active surface area compared to conventionalferric organic compound complexes.

This invention provides a use of a form of ferric organic compound orferric citrate to treat a subject suffering from a disorder responsiveto ferric organic compound therapy. In an embodiment, the disorderincludes but is not limited to hyperphosphatemia or metabolic acidosis.

This invention provides a method of treating a subject suffering from adisorder responsive to ferric organic compound therapy comprisingadministering to the subject a therapeutically effective amount of aform of ferric organic compound or ferric citrate as described above. Inan embodiment, the disorder includes but is not limited tohyperphosphatemia or metabolic acidosis.

This invention provides a form of ferric organic compound or ferriccitrate as describe above, wherein said form of ferric organic compoundor ferric citrate is in an orally administrable form which includes, butis not limited to, a powder, a suspension, an emulsion, a capsule, agranule, a troche, a pill, a liquid, a spirit or a syrup. In anembodiment, the ferric organic compound or ferric citrate is in a formor in an acceptable carrier suitable for topical, sublingual, parenteralor gastrointestinal administration, or aerosolization.

This invention provides a composition comprising a form of ferricorganic compound or ferric citrate as describe above and a suitablecarrier.

As used herein, the term suitable carrier includes, but not limited to,any suitable carrier for administering pharmaceutical compositions knownto those of ordinary skill in the art. The type of carrier will varydepending on the mode of administration.

With regards to compositions for parenteral administration (e.g.subcutaneous injections), the term suitable carrier includes but notlimited to water, saline, alcohol, a fat, a wax or a buffer.

With regards to compositions for oral administration, the term suitablecarrier includes but not limited to any of the above carriers or a solidcarrier, such as mannitol, lactose, starch, magnesium stearate, sodiumsaccharine, talcum, cellulose, glucose, sucrose, and magnesiumcarbonate.

Biodegradable microspheres (e.g., polylactate polyglycolate) may also beemployed as carriers for the pharmaceutical compositions of thisinvention.

This invention provides a pharmaceutical composition comprising a formof ferric organic compound or ferric citrate as describe above and apharmaceutically acceptable carrier. In another embodiment, thepharmaceutically acceptable carrier comprises a controlled releaseformulation.

This invention provides a pharmaceutical composition comprising aneffective amount of a form of ferric organic compound or ferric citrateas describe above for treating disorders responsive to ferric organiccompound therapy. In an embodiment, the disorder includes but is notlimited to hyperphosphatemia and metabolic acidosis.

As used herein, pharmaceutically acceptable carriers includes, but isnot limited to, a liquid, an aerosol, a capsule, a tablet, a pill, apowder, a gel, an ointment, a cream, a granule, water, phosphatebuffered saline, Ringer's solution, dextrose solution, serum-containingsolutions, Hank's solution, other aqueous physiologically balancedsolutions, oils, esters, glycols, biocompatible polymers, polymericmatrices, capsules, microcapsules, microparticles, bolus preparations,osmotic pumps, diffusion devices, liposomes, lipospheres, cells orcellular membranes.

1. General Method of Synthesis of Novel Forms of Ferric OrganicCompounds

Referring to FIG. 1, synthesis scheme 10 is a general method forsynthesizing novel forms of ferric organic compounds. The startingmaterials, as indicated in box 20, comprise soluble ferric iron salts.The soluble ferric iron salts can comprise ferric chloride hexahydrate(FeCl₃6H₂O), as indicated in box 21, or any other suitable solubleferric iron salt. Next, an alkaline metal hydroxide (box 30) is added ata specific rate and temperature to the soluble ferric iron salt. Theaddition of the alkaline metal hydroxide at a specific rate, preferablybetween about 10 ml/min and about 20 ml/min, and temperature range,preferably below 40° C., results in the formation of a uniform polyironoxo colloidal suspension. The alkaline metal hydroxide can comprisesodium hydroxide, potassium hydroxide, or any other suitable alkalinemetal hydroxide as indicated in box 31. The colloidal suspensionprecipitate is collected and rinsed (box 40) with distilled water toremove any soluble impurities. After rinsing, the precipitate isre-suspended and, as indicated in box 50, crystalline organic acid isadded to the precipitate and heated to a particular temperature range,preferably between about 80° C. to about 90° C. The organic acid cancomprise any suitable organic acid. Box 51 lists some of the possibleorganic acids which can be used, including, but not limited to, citricacid, acetic acid, isocitric acid, succinic acid, fumaric acid, andtartaric acid. The addition of the organic acid allows the acid to formcomplexes with the precipitate in solution. At box 60, the ferricorganic compound is precipitated out of solution with an organic solventto form a novel form of ferric organic compound (box 70). Variousorganic solvents can be used, including, but not limited to, thesolvents described in box 61, such as ethanol, methanol, butanol,acetone, isopropyl alcohol, tetrahydrofuran, or any other suitableorganic solvent.

2. Solubility Profile of Novel Forms of Ferric Organic Compounds

The inventors have found that the novel forms of ferric organiccompounds produced according to the methods described above are moresoluble than commercially available ferric organic compounds, over awider range of pH levels. This increase in solubility of the novelferric organic compounds is believed to be a result of the uniquesignificantly large active surface area of the novel forms of ferricorganic compounds. For example, at pH 8.0, the intrinsic dissolutionrate of novel form of ferric citrate is 3.08 times greater than thecommercially available ferric citrate. See Table 3.

3. Use of Novel Forms of Ferric Organic Compounds in the Treatment ofDisorders

The novel forms of ferric organic compounds are useful in the treatmentof hyperphosphatemia, metabolic acidosis, and any other disordersresponsive to ferric organic compound therapy. Because the novel formsof ferric organic compounds are more soluble than commercially availableferric organic compounds, smaller amounts of the ferric organiccompounds can be used to effectively treat patients suffering from suchdisorders.

Improved aqueous solubility is particularly relevant to the use of thenovel forms of ferric organic compounds in the treatment of disordersresponsive to ferric organic compound therapy. Because the novel formsof ferric organic compounds are more soluble, they will be moreeffective when taken orally, and therefore can be taken in lower doses.The novel forms of ferric organic compounds are more soluble over awider pH range than commercially available ferric organic compounds,therefore the novel forms of ferric organic compounds can be moreeffective by being soluble in the small intestine. For example, in anexperiment simulating the alkaline condition in the small intestine, thenovel form of ferric citrate showed better dissolution rate than thecommercially available ferric citrate. It is suggested that the novelform of ferric citrate can be more effective by being more soluble inthe small intestine. See Table 3. As a result, patients can take lowerdoses of medication with lower incidences of side effects.

In one embodiment of the invention, the novel form of ferric citrate hasa significantly higher rate of aqueous solubility under physiologicalconditions than commercially available forms of ferric citrate, andtherefore the novel form is believed to provide a significantimprovement in the orally effective use of ferric citrate at a reduceddosage. By reducing the orally effective dose of ferric citrate, it isbelieved that the novel form of ferric citrate will provide a lowerincidence of ulcerative gastrointestinal adverse effects associated withcommercially available ferric citrate compounds. In addition, it isbelieved that the increased rate of dissolution of the novel form offerric citrate will provide a more rapid onset of action in binding todietary phosphate.

The novel forms of ferric organic compounds can be administered in anumber of forms, including orally administrable forms, which cancomprise the novel forms of ferric organic compounds alone or incombination with a pharmaceutically acceptable carrier. The orallyadministrable form includes, but is not limited to, a tablet, a powder,a suspension, an emulsion, a capsule, a granule, a troche, a pill, aliquid, a spirit, or a syrup. The composition can be administered tohuman beings or other animals suffering from illnesses responsive toferric organic compound therapy.

EXAMPLES

In examples which are intended to illustrate embodiments of theinvention but which are not intended to limit the scope of theinvention:

1) Method of Making A Novel Form of Ferric Citrate

In one embodiment of the invention, the starting materials for making anovel form of ferric citrate comprise a 1.85M solution of ferricchloride hexahydrate (FeCl₃6H₂O). A volume of 5M sodium hydroxidenecessary to produce a 1:3 ratio of ferric iron to hydroxide ion isadded to the ferric chloride hexahydrate solution at a rate of less than20 ml per minute, preferably between about 10 ml per minute and about 20ml per minute. The temperature of the mixture is maintained below 40°C., preferably between about 10° C. to about 40° C., while the sodiumhydroxide is added to form a polyiron oxide colloidal suspension offerric hydroxide. The pH of the suspension is measured while the sodiumhydroxide is added. Once the pH is above 7.0, the suspension is cooleduntil it is less than 30° C., preferably between about 10° C. to about30° C. The suspension is then filtered through a 1 mm pore filter tobreakup aggregates and remove large particles of ferric hydroxideprecipitate. The filtered ferric hydroxide suspension is thencentrifuged. The supernatant is discarded, then the precipitated ferrichydroxide is centrifuged again to remove any remaining supernatant. Theferric hydroxide precipitate is then resuspended with distilled water.The centrifugation-resuspension steps are repeated two more times towash the ferric hydroxide precipitate and remove water solubleimpurities. The resulting ferric hydroxide precipitate is thenhomogenized.

An amount of citric acid necessary to produce a 1:1 ratio of ferric ironto citrate is added to the precipitate. The mixture is heated to betweenabout 80° C. to about 90° C. in an oil bath until the color of themixture changes from orange-brown to a clear black-brown, or until allof the ferric hydroxide precipitate is dissolved. The reaction is cooleduntil it is less than 30° C., preferably between about 10° C. to about30° C., and the pH is measured to determine that it is within 0.8 and1.5. The reaction is centrifuged, and the supernatant is collected.

The novel form of ferric citrate is precipitated from the supernatant byadding 5 volumes of organic solvent. Various organic solvents can beused, including ethanol, methanol, butanol, acetone, isopropyl alcohol,or tetrahydrofuran. Table 1 below lists the relative amounts of ferriccitrate formed in solution using various solvents. Once the solvent isadded, the mixture is stirred until a light beige precipitate forms. Thesuspension is centrifuged and the supernatant is discarded. Theprecipitate is washed and centrifuged with the solvent two more times.The precipitate is then dried in a vacuum oven for 8 to 16 hours atambient temperature or by any other suitable industrial processes suchas fluidized-bed drying. The dried precipitate is ground with a mortarand pestle and dried for another 8 to 24 hours at ambient temperature.The fine precipitate is finely ground by milling again and screenedthrough a 45 mesh size (35 micron) sieve. The novel form of ferriccitrate powder is dried in the vacuum oven again or fluidized-bed dryingagain and dried at ambient temperature until 1 hour of drying leads toless than 0.25% loss in weight.

TABLE 1 Comparison of relative percentage of novel form of ferriccitrate formed by different organic solvents Relative % of Novel Form ofFerric Solvent Citrate Formed in Solution ferric citrate 100 isopropylalcohol 89.7 tetrahydrofuran 90.6 butanol 99.8 methanol 101.2 acetone99.8 ethanol 95.8

The following chemical equations represent the chemical reactionsdescribed in the specific embodiment of the method for making the novelform of ferric citrate:FeCl₃+3NaOH→Fe(OH)₃+3NaCl  (1)Fe(OH)₃+C₆H₈O₇→Fe(C₆H₅O₇)+3H₂O  (2).2) Physical Properties of Novel Form of Ferric Citrate

The chemical purity of the novel form of ferric citrate was ascertainedby negative-ion liquid chromatography or mass spectrometry (LC/MS)flow-injection method which provided measurement of all mass ionspresent in solution. Specifically, the mass ions at m/z 243.6 for thenovel form of ferric citrate and at m/z 190.6 for citric acid amongstother related and non-related ions in solution were observed. The use ofLC/MS analysis also enabled the observation of a number of ferriccitrate related and non-related substances and permitted thedetermination of the relative purity of the novel form of ferric citrateamongst the minor impurities. Such information is critical forapplication of the novel form of ferric citrate as pharmaceutical gradematerial. The representative chemical purity of the novel form of ferriccitrate from three process batches are presented in Table 2.

TABLE 2 Representative chemical purity of novel form of ferric citrateComponents of Novel form of Ferric citrate Percent w/w anhydrous basisPurity of solid state 99.4% 99.6% 99.5% ferric citrate Assay contentpurity of 73.1% 78.3% 76.2% ferric citrate and ferric citrate wateradduct in solution state Assay content of citric 10.3% 10.0% 8.0% acidin solution state Assay content of ferric 26.3% 21.3% 23.3% citraterelated substances in solution state Assay content of ferric 0.6% 0.4%0.5% citrate non-related substances in solution state

The intrinsic dissolution rates of commercially available ferric citratewere compared with the novel form of ferric citrate. The intrinsicdissolution rate is defined as the dissolution rate of pure substancesunder the condition of constant surface area. The dissolution rate andbioavailability of a drug substance is influence by its solid stateproperties: crystallinity, amorphism, polymorphism, hydration,solvation, particle size and particle surface area. The measuredintrinsic dissolution rate is dependent on these solid-state propertiesand is typically determined by exposing a constant surface area of amaterial to an appropriate dissolution medium while maintaining constanttemperature, stirring rate, and pH. The intrinsic dissolution rates arepresented in Table 3.

TABLE 3 Intrinsic dissolution rates of ferric citrate at 37° C. insolutions of pH 8 Mean Rate of Intrinsic Intrinsic Acetone DissolutionDissolution Addition Rates Rates Sample (ml/min) (mg/cm2/min)(mg/cm2/min) RFS-12 (sigma/ 10.0 0.83 0.83 commercially available)STM-134 10.0 1.88 3.08 (reference material) PAN031203A 10.0 3.82(experimental batch 1) PAN031203B 10.0 4.00 (experimental batch 2)PAN031203C 9.5 2.68 (experimental batch 3) PAN031203D 40 2.95(experimental batch 4) PAN031203E 4.4 3.13 (experimental batch 5)

FIG. 2 is a graph which compares the dissolution profile of the novelform of ferric citrate to the dissolution profile of commerciallyavailable ferric citrate compounds.

The intrinsic dissolution rates of the novel form of ferric citrateproduced by the method of the invention, on average, are approximately3.8 times greater than that determined for a commercially availableferric citrate material. This increase in dissolution rate of the novelform of ferric citrate is believed to be a result of the significantlylarge active surface area of the novel form of ferric citrate comparedto commercially available materials. For example, the BET active surfacearea of novel form of ferric citrate is at least 16 times larger thanthe commercially available ferric citrate. See Table 4.

A BET active surface area isotherm of the novel form of ferric citrateis shown in FIG. 3. The analysis of active surface area is based on BETtheory which describes the phenomenon of mass and energy interaction andphase changes during gas adsorption onto solid surfaces and in porespaces. In BET active surface area measurement, the volume of amonolayer of gas is determined which allows the surface area of thesample to be determined using the area occupied by a single layer ofadsorbed gas molecule. Table 4 is a comparison of the active surfacearea of the novel form of ferric citrate compared to the active surfacearea of commercially available ferric citrate compounds.

TABLE 4 BET active surface areas of various forms of ferric citrate MeanBET Dissolution Active Rates Surface Sample (mg/cm2/min) Area RFS-12-1(sigma/commercially 0.76 0.61 available) RFS-12-2 (sigma/commerciallyavailable) STM-134-1 (reference material 1) 2.47 16.17 STM-134-2(reference material 2) STM-182-1 (lab-scale 500 g batch 1) 2.61 19.85STM-182-2 (lab-scale 500 g batch 2)

The x-ray diffraction spectra of the novel form of ferric citrate arepresented in FIG. 4, showing diffraction features characteristics ofcrystalline materials. The thermogravimetric analysis of the novel formof ferric citrate is presented in FIG. 5, showing heat absorptionisotherms characteristics of the novel material.

As will be apparent to those skilled in the art in the light of theforegoing disclosure, many alterations and modifications are possible inthe practice of this invention without departing from the spirit orscope thereof. Accordingly, the scope of the invention is to beconstrued in accordance with the substance defined by the followingclaims.

1. A solid form of ferric citrate having a formula of C₆H₅O₇Fe and anintrinsic dissolution rate between 1.9 and 4.0 mg/cm²/min, as determinedby the USP intrinsic dissolution assay in water, wherein the solid formof ferric citrate is synthesized by a method comprising: (a) adding analkaline metal hydroxide solution to a ferric chloride solution; (b)isolating a ferric hydroxide precipitate; (c) forming a suspension ofthe ferric hydroxide precipitate in water; (d) adding citric acid to thesuspension and forming a ferric-citric acid solution by heating saidsuspension with said citric acid; and (e) precipitating the solid formof ferric citrate by mixing the ferric-citric acid solution with anorganic solvent.
 2. The solid form of ferric citrate of claim 1, whereinthe alkaline metal hydroxide is aqueous sodium hydroxide or aqueouspotassium hydroxide.
 3. The solid form of ferric citrate of claim 1,wherein the ferric chloride solution is an aqueous solution, or isprepared from ferric chloride hexahydrate.
 4. The solid form of ferriccitrate of claim 1, wherein the organic solvent is ethanol, methanol,butanol, acetone, isopropyl alcohol or tetrahydrofuran.
 5. The solidform of ferric citrate of claim 1, wherein the compound has a BET activesurface area exceeding 16 m²/g.
 6. The solid form of ferric citrate ofclaim 1, wherein the compound is used for treating disorders responsiveto ferric organic compound therapy.
 7. The solid form of ferric citrateof claim 6, wherein the disorder is hyperphosphatemia or metabolicacidosis.
 8. The solid form of ferric citrate of claim 7, wherein thedose for treating the disorder is 3 g/day to 6 g/day.
 9. The solid formof ferric citrate of claim 1, wherein the compound is for oraladministration as a tablet, powder, capsule, granule, troche or pill.10. A pharmaceutical composition comprising the solid form of ferriccitrate of claim 1 and a pharmaceutically acceptable carrier.
 11. Thepharmaceutical composition of claim 10, wherein the solid form of ferriccitrate has a BET active surface area exceeding 16 m²/g.
 12. Thepharmaceutical composition of claim 10, wherein the composition is usedfor treating disorders responsive to ferric organic compound therapy.13. The pharmaceutical composition of claim 12, wherein the disorder ishyperphosphatemia or metabolic acidosis.
 14. The pharmaceuticalcomposition of claim 13, wherein the dose of the solid form of ferriccitrate for treating the disorder is 3 g/day to 6 g/day.
 15. Thepharmaceutical composition of claim 10, wherein the composition is fororal administration as a tablet, powder, capsule, granule, troche orpill.